Synergies for Cancer Treatments: August 2019

Treatment will depend on the stage of the cancer and may include surgery, chemotherapy, and radiation.

Surgery

CYTALUX™: FDA-approved prescription medication that is given prior to surgery to adult patients who have ovarian cancer. It helps surgeons visualize ovarian cancer lesions during surgery.
Surgery for Recurrent Ovarian Cancer Does Not Improve Survival. {study}. Findings suggest that women who have additional surgery may fare worse than those who do not.

Chemotherapy

* → potential synergy

Cisplatin (1978)

→ Curcumin {study}
→ Melatonin {study}
→ Berberine {study}
→ Resveratrol {study}
→ Ursolic Acid {study}
→ Ashwagandha {study}
→ Bitter Melon {study}
→ Honokiol {study}
→ Low dose Naltrexone {study}

Altretamine (1990)
Carboplatin (1991)

→ see cisplatin
→ Vitamin D3 {study}

Paclitaxel (Taxol)(1992)

→ I3C + EGCG {study}
→ Modified Citrus Pectin 🛈 {study┃study}
→ Feverfew {article}
→ Boswellia {study}
→ Lapachone {study}

Topotecan (1996)

Low dose of daily Topotecan combined with bevacizumab {ref}

Pegylated Liposomal Doxorubicin, PLD (2000)

→ Curcumin {study}
→ Melatonin {study}

Gemcitabine + Carboplatin (2006) {reduced-dose-doublet schedule}
Bevacizumab (Avastin) + chemo platinum resistant (2014) {article phase III trial}
Bevacizumab + chemo platinum sensitive (2016)

→ Metformin {study}

Rucaparib (2016) PARP inhibitor {ref}
Niraparib (2017) PARP inhibitor {clinical trial results} Data from the ENGOT-OV16/NOVA study show no difference in overall survival (OS) for patients with platinum-sensitive recurrent ovarian cancer who received poly (ADP-ribose) polymerase (PARP) inhibitor Niraparib maintenance therapy and those who did not. {ref}
Olaparib (2018) PARP inhibitor

→ Alantolactone (selective STAT3 inhibitor) {study}
No Overall Survival Difference With PARP Inhibitor Maintenance Therapy in Ovarian Cancer {post}

Pembrolizumab, Bevacizumab, and Cyclophosphamide{clinical trial/article} Complete responses were observed in 7.5% of women, whereas partial responses occurred in 40% of women, and 47.5% had stable disease as a response to the treatment. In addition, the ORR was 47.5%, with 95% obtaining clinical benefit from the treatment and 25% experiencing a durable response. The median PFS throughout the trial was 10 months.

Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment

Chemotherapy vs 40 mg tamoxifen in platinum-resistant ovarian cancer: a phase III, randomized, multicentre trial (Ovaresist): chemotherapy experienced more toxicity and poorer Health-related Quality of Life compared with tamoxifen There was no difference in OS between the treatment arms.{ref}

Identification of potent SENP1 inhibitors that inactivate SENP1/JAK2/STAT signaling pathway and overcome platinum drug resistance in ovarian cancer {ref}

Alternative or Complementary treatments (Integrative Therapy)

Supplements

Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use. {study}

Vitamin D {study}

Honokiol and Magnolol {study}

AHCC: https://www.ncbi.nlm.nih.gov/pubmed/29111786

Amla: Emblica officinalis Extract Induces Autophagy and Inhibits Human Ovarian Cancer Cell Proliferation, Angiogenesis, Growth of Mouse Xenograft Tumors "In this study we determined that Amla extract (AE) has anti-proliferative effects on OC cells under both in vitro and in vivo conditions. We also determined the anti-proliferative effects one of the components of AE, quercetin, on OC cells under in vitro conditions. AE did not induce apoptotic cell death, but did significantly increase the expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. Quercetin also increased the expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. AE also significantly reduced the expression of several angiogenic genes, including hypoxia-inducible factor 1α (HIF-1α) in OVCAR3 cells. AE acted synergistically with cisplatin to reduce cell proliferation and increase expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. AE also had anti-proliferative effects and induced the expression of the autophagic proteins beclin1 and LC3B-II in mouse xenograft tumors. Additionally, AE reduced endothelial cell antigen – CD31 positive blood vessels and HIF-1α expression in mouse xenograft tumors."

Artemisinin: https://www.ncbi.nlm.nih.gov/pubmed/30395153

Astragalus

Sulforaphane: https://www.spandidos-publications.com/ijmm/42/5/2447

Lycopene: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489781/: "Lycopene decreased the expression of the ovarian cancer biomarker, CA125. The anti-metastatic and anti-proliferative effects were accompanied by down-regulated expression of ITGA5, ITGB1, MMP9, FAK, ILK and EMT markers, decreased protein expression of integrin α5 and reduced activation of MAPK."

Green Tea: Green tea consumption enhances the survival of epithelial ovarian cancer. "There were 81 (77.9%) of 104 tea-drinkers who survived to the time of the interview, compared to only 67 women (47.9%) still alive among the 140 non-drinkers." {Study}

I3C + EGCG: https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4792-9: "Long-term usage of I3C and EGCG may represent a new promising way of maintenance therapy in advanced ovarian cancer patients, which achieved better treatment outcomes."

I3C: {ref}

Baicalin https://www.ncbi.nlm.nih.gov/pubmed/29039573

Graviola {ref}

Modified Citrus Pectin

Zinc {study}

Helixor M (mistletoe) {case report}

Tripterygium Wilfordii + curcumin / milk thistle / ascorbic acid

Fucoidan

Propolis

Calcitriol {study│study│study}

DHA Dihydroartemisinin + Curcumin: {study}

Vitamin K2 {study}

Beta-Caryophyllene (copaiba){study}

Delta-Tocotrienol, a form of vitamin E derived from annatto seeds, along with Avastin (Bevacizumab) doubled the survival rate and stabilized the disease in 70% of chemotherapy-resistant ovarian cancer patients {study}

Nobiletin {study}

Epigenetic mechanisms

Butyrate: genes related to growth and invasiveness are repressed by sodium butyrate in ovarian carcinoma cells {article}

Repurposed drugs🟪

Clarithromycin synergizes with cisplatin to inhibit ovarian cancer growth in vitro and in vivo
Repurposing mebendazole in combination with PRIMA1 MET for ovarian cancer therapy
Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH
Screening a library of approved drugs reveals that prednisolone synergizes with pitavastatin to induce ovarian cancer cell death
Metformin Antitumoral Effects of Metformin in Ovarian Cancer, Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells
Cimetidine {ref}
Ivermectin {study}
Orlistat {study}
Pazopanib: a tyrosine kinase inhibitor initially developed to treat renal cell carcinoma. It has since been repurposed to treat soft tissue sarcomas, ovarian cancer, and thyroid cancer.

⌘ Natural PARP inhibitors

Puerarin Sources: Kudzu Root Extract
Chlorogenic acid Sources: Green coffee bean extract🛈
Biochanin Sources: Red clover
Phloretin Sources: Manchurian apricot (Prunus mandshurica)
Hesperetin http://nutrition.merschat.com/foods-by-nutrient.cgi?Nutr_No=759
Quercetin capers, red onions, unsweetened dark chocolate(85% cocoa), more
Quercetin: a natural compound for ovarian cancer treatment {study}
Niacinamide Available as a supplement study
Naringin Grapefruit*, citrus fruit, bergamot, sour orange, tart cherries, tomatoes, cocoa, oregano, oil of oregano, water mint, Drynaria, and beans.

*Eating grapefruit or drinking grapefruit juice while taking certain medications can lead to higher levels in your blood and more side effects. With some drugs, even small amounts of grapefruit can cause severe side effects. Therefore, the combination should be avoided.

⌘ HDAC Inhibition

HDACi
"Ovarian clear cell carcinoma (OCCC) is associated with a frequent loss in ARID1A function. ARID1A reportedly suppresses histone deacetylase (HDAC)6 in OCCC directly" {article}
Natural product-derived therapy for gynecologic cancers (HDAC6) "pharmacological formulations encompassing “Berberine (BER), Dihydroartemisinin (DHA), and Curcumin (CUR) or their analogues, either alone or in combination with other known anticancer drugs” may be used to inhibit the progression of ARID1A-mutated ovarian cancers ". 46–70% of clear cell carcinomas and 30–46% of endometrioid carcinomas harbor ARID1A mutations. {article}
Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High-Grade Serous Ovarian Cancer Cell Line {Ref}
Scriptaid (HDACi) + bortezomib (proteasome inhibitor): {study} ⚠ Green tea polyphenols block the anticancer effects of bortezomib
Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer {study}

⌘ Angiogenesis

Ovarian cancer ˃ vascular endothelial growth factor (VEGF) driven tumor

Caffeine
Theobromine:{study| study | article}, Foods highest in Theobromine also{pgp inhibitor}
Ashwagandha
Viscum album
Curcumin
Green tea
Ginger
Grape seed extract
Ginkgo Biloba
Magnolia officinalis

⌘ mTOR inhibition

Vistusertib

https://www.ncbi.nlm.nih.gov/pubmed/30016392:"The study found that just over half of the ovarian cancer patients saw the size of their tumour shrink by at least 30%. It also saw an average of nearly six months progression-free survival, meaning there was no further tumour growth in this period of time. These outcomes are particularly significant as previously this type of ovarian cancer would have been resistant to all types of standard treatment."

Curcumin
Rapamycin

https://pubmed.ncbi.nlm.nih.gov/21610153/

⌘ FAK inhibition

FAK Protein Linked to Chemo Resistance in Ovarian Cancer

Antrodia camphorata

Cryptotanshinone Inhibits Ovarian Tumor Growth and Metastasis by Degrading c-Myc and Attenuating the FAK Pathway {study}

⌘ ALDH1A inhibitor

https://www.tocris.com/products/673-a_6934

⌘ MIP-1β inhibition

"macrophages produce a protein called MIP-1β, which causes the mesothelial cells to produce more of an adhesion protein called P-selectin. P-selectin, in turn, allows the cancer cells to stick." {article}

⌘ HER2 overexpression

Magnolol down-regulates HER2 gene expression, leading to inhibition of HER2-mediated metastatic potential in ovarian cancer cells. {study}

honokiol, magnolol also downregulate P-gp expression {study}

Danshen
Echinacea
Curcumin

⌘ MMP-9 overexpression

https://www.ncbi.nlm.nih.gov/pubmed/28859117: "results suggest that the phosphorylation of STAT3 regulates MMP-9 production in ovarian cancer, which might be responsible for its invasiveness and metastasis."

⌘ CD36 downregulation

Cruciferous "Subgroup analyses showed only yellow and cruciferous vegetables to significantly favor survival" {ref|ref}

Relevant studies, articles, and reviews

https://www.researchgate.net/figure/The-role-of-vitamin-D-and-vitamin-D-receptor-VDR-in-gynecological-cancers-Endogenous_fig1_321212073

Synergies for Cancer Treatments

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